Cheng Sheue-Yann
a National Cancer Institute, Laboratory of Molecular Biology, 37 Convent Dr., Room 5128, Bethesda, MD 20892-4264, USA.
Expert Rev Endocrinol Metab. 2007 Jan;2(1):47-57. doi: 10.1586/17446651.2.1.47.
Thyroid hormone nuclear receptors (TRs) mediate thyroid hormone's activities in growth, differentiation, and development. Two TR genes (α and β ) encode four thyroid hormone-binding receptors that regulate target gene expression. Mutations of the TRβ gene cause the genetic syndrome of resistance to thyroid hormone. Studies indicate a close association between TRβ mutations and several human cancers, suggesting their oncogenic role. A TRβ gene knock-in mutant mouse (TRβ mouse) that spontaneously develops thyroid cancer allows elucidation of the oncogenic functions in vivo. TRβPV is a potent dominant negative mutant identified in a resistance to thyroid hormone patient. Molecular studies indicate that the PV mutant mediates its oncogenic activities via nucleus-initiated transcription and novel extranuclear actions. Thus, the deleterious effects of the gene mutations go beyond resistance to thyroid hormone and are more severe and extensive than previously envisioned. This newly identified oncogene exerts its tumorigenic effects via multiple signaling mechanisms.
甲状腺激素核受体（TRs）介导甲状腺激素在生长、分化和发育过程中的活性。两个TR基因（α和β）编码四种甲状腺激素结合受体，这些受体调节靶基因的表达。TRβ基因突变会导致甲状腺激素抵抗的遗传综合征。研究表明TRβ突变与几种人类癌症密切相关，提示它们的致癌作用。一种自发发生甲状腺癌的TRβ基因敲入突变小鼠（TRβ小鼠）有助于阐明体内的致癌功能。TRβPV是在一名甲状腺激素抵抗患者中鉴定出的一种强效显性负性突变体。分子研究表明，PV突变体通过细胞核启动的转录和新的核外作用介导其致癌活性。因此，基因突变的有害影响超出了对甲状腺激素的抵抗，且比之前预想的更为严重和广泛。这个新发现的癌基因通过多种信号机制发挥其致瘤作用。
